The following description provides a summary of information relevant to the present disclosure and is not an admission that any of the information provided or publications referenced herein is prior art to the present disclosure.
Severe itching negatively impacts the quality of life of millions of people every day. Severe itching may be associated with various health conditions, including pruritic skin conditions, such as scabies, eczema, xerosis, psoriasis and urticaria, as well as systemic conditions, including chronic hepatic or renal disease and lymphoma. Similarly, pain is a common occurrence, being one of the major reasons for visits to a physician. Pain may be associated with numerous types of injuries or conditions, and failure to treat acute pain may lead to chronic pain issues, as well as immune and metabolic disorders. In addition to reducing the quality of life for the individual suffering from pruritus and/or pain, there is a significant impact on healthcare budgets, particularly in relation to pruritic skin conditions, as well as, chronic pain disorders. Current efforts to manage or treat pruritus and/or pain are widely recognized as being inadequate.
Neurophysiological research has confirmed the distinctiveness of itch pathways in comparison with those of pain. The itch sensation is perceived and transmitted by dedicated C neurons which are distinct from the nociceptors that process pain sensation (Schmelz, Neurosci. Biobehav. Rev. doi:10.1016/j.neubiorev.2008.12.004, 2009). The dedicated C neurons then transmit the itch stimulus to a specialized class of dorsal horn neurons projecting to the thalamus (Stander and Schmelz, Eur. J. Pain 10:473, 2006). There is believed to be no special itch receptor on peripheral nerve endings and the specificity of itch C neurons is based on their spinal connections to the itch pathway. Differences are observed in the brain activation patterns between itch and pain, such as an absence of detectable activation of the thalamic and somatosensory cortex of the parietal lobe from itch sensation (Yosipovitch et al., Lancet 361:690, 2003).
Pain is generally classified as either acute or chronic. Acute pain is commonly a response to tissue damage, characterized as short-lived and resolves as the initial damage heals. Chronic pain is persistent and may have no apparent association with a traumatic event. Pain may further be classified based on the mechanistic origin of the pain and includes nociceptive and non-nociceptive. Nociceptive pain is mediated by specific receptors (nociceptive receptors) that are activated by a specific stimulus (injury, inflammation, chemical, etc). Nociceptive pain may further be classified as somatic or visceral. Somatic pain occurs in tissues such as skin, muscle, joints, bones, or ligaments. Somatic pain is generally sharp and localized. Current treatments include use of opioids and non-steroidal anti-inflammatory drugs (NSAIDS). Visceral pain occurs in internal organs. It is frequently a poorly localized pain and is generally treated with opioids.
Non-nociceptive pain may be further broken down into neuropathic or sympathetic. Neuropathic pain may arise in the peripheral or central nervous system. Neuropathic pain may be associated with degenerative conditions, inflammation, or infectious diseases. This type of pain results in hypersensitivity (hyperalgesia) and is frequently described as shooting or burning. Treatment options include N-methyl-D-aspartate (NMDA) antagonists, anti-arrhthymics, anti-convulsants, or anti-depressants. Neuropathic pain is frequently resistant to conventional analgesics. Sympathetic pain arises in the sympathetic nervous system as well as the peripheral and central nervous systems and is generally associated with some type of injury. The site of injury may show increased hypersensitivity and abnormal temperature. Treatment generally involves a multi-drug regimen including sympathetic nerve blocks, vasodilatation, anti-convulsives, anti-arrhthymics, and anti-depressants.
Routine and prolonged treatment of pain with opioid analgesics is not recommended because of the concern for potential addiction, side effects, tolerance, and dependency on the opioid. Opioid side effects can include nausea, vomiting, constipation, respiratory depression, etc. With many current treatments there exists a lack of efficacy, serious side effects, and inability of drug delivery methods to help in adequate pain control. These issues support the need for better pain control therapeutics.
Although itch and pain are clearly distinct sensations, there are important interactions between itch and pain. It is well known that itch can be reduced by the painful sensation caused by scratching. Yet, analgesics, such as opioids, by acting to diminish pain sensations, can actually enhance itch sensation. Thus, some therapeutics for pain can exacerbate itch symptoms further supporting the need for better therapeutics with the potential to treat both itch and pain.
Nerve growth factor (NGF) is one of a family of neurotrophic cytokines or neurotrophins. Neurotrophins play a key role in the development and maintenance of both the peripheral and central nervous system by controlling cell survival, differentiation, and apoptosis. In addition to these nervous system functions, NGF has also been shown to increase the release of histamine, the production of mast cells, and the growth and differentiation of B lymphocytes. NGF has also been shown to modulate the basophilic production of certain lipid mediators. The apoptosis of neutrophils may also be suppressed by NGF. All of these factors suggest a role for NGF in the immune system as well as the nervous system.
The NGF beta chain (β-NGF) is solely responsible for the nerve growth stimulating activity of NGF. In the cell, β-NGF exists as a dimer and binds to two types of cell surface receptors in neuronal and non-neuronal cells. The tertiary structure of the protein is based on three cystine disulfides and two anti-parallel, β-strands. The amino acid homology of the human, mouse, and rat proteins are about 90%. β-NGF, like all of the neurotrophins, binds to the p75 cell receptor with nM affinity. β-NGF also binds to one of the tyrosine kinase receptors (Trk) in particular, TrkA, with pM affinity. Reaction with the p75 receptor can induce cell death while binding to TrkA promotes cell survival. β-NGF binding to TrkA leads to phosphorylation of the receptor and internal cellular proteins. β-NGF is internalized by receptor-mediated endocytosis. Trk receptors are found in a wide range of non-neuronal tissues.
Nerve growth factor (NGF) released from keratinocytes in the skin is one of the major mediators that increase dermal nerve density and affect morphology by, among other things, promoting sprouting of nerve fibers (Schmelz, Neurosci. Biobehav. Rev. doi:10.1016/j.neubiorev.2008.12.004, 2009). Patients with chronic pruritus have been found to exhibit increased intradermal nerve fiber density. Further, NGF has been found to increase sensitivity of peripheral neurons by, among other things, triggering the receptor of NGF, tyrosine kinase TrkA (Stander and Schmelz, Eur. J. Pain 10:473, 2006).
The importance of NGF in mediating pruritus as well as pain is exhibited in the high concentrations of NGF measured in atopic conditions, which may be symptomized by both pruritus and pain. Patients with atopic dermatitis have greatly increased serum levels of NGF which positively correlate with the severity of the condition. Patients with contact dermatitis have higher local NGF concentrations and patients with prurigo nodularis also exhibit higher NGF levels and TrkA activation levels (Schmelz, Neurosci. Biobehav. Rev. doi:10.1016/j.neubiorev.2008.12.004, 2009).
The effects of anti-NGF antibodies administered systemically by intraperitoneal injection on symptoms in a mouse model for atopic dermatitis having been studied and results “suggest that anti-NGF antibodies block the effects of NGF on the periphery of the nervous system and suppress epidermal innervations, dermatitis and scratching behavior” (Takano et al. J. Pharmacol Sci 99:277:284, 2005). Yet, the study found that anti-NGF antibodies did not alter serum NGF levels, did not decrease the NGF concentration in the skin areas tested, and did not completely suppress scratching behavior. Thus, a need to more completely reduce or eliminate itching associated with atopic dermatitis remains.
A growing body of evidence indicates that NGF functions as a mediator of certain pain states. It has been shown that anti-NGF antibodies can produce a sustained thermal and chemical analgesic effect, as well as block the hyperalgesia which develops from carrageenan-induced inflammation (McMahon et al., Nat. Med. 1:774, 1995). Studies of a small molecule NGF receptor antagonist for blockading the bioactivity of NGF have indicated an analgesic effect on neuropathic and inflammatory pain states (Owolabi et al., J. Pharmacol. Exp. Ther. 289:1271, 1999)). In the Owolabi et al. study, the analgesic effect of the small molecule NGF activity inhibitor may be less than that of morphine depending on the route of administration. Since opioids, such as morphine, have many unwanted side-effects, a need remains for providing analgesia in the variety of pain states mediated by NGF which allows flexibility in effective administration.